ABSTRACT Alzheimer's disease (AD) is the most common neurodegenerative disease affecting millions of Americans. Neurons have a large amount of polyunsaturated fatty acids in membrane phospholipids that are vulnerable to attack by reactive oxygen species to result in lipid peroxidation. Lipid peroxidation is increased in AD brains and is believed to play a key role in driving neurodegeneration of AD. However, supplementation of lipid soluble antioxidants yields only mixed results in clinical trials. So the importance of lipid peroxidation in AD remains unproven. Glutathione peroxidase 4 (Gpx4) is a glutathione peroxidase that can suppress lipid peroxidation by directly reducing phospholipid hydroperoxides in membranes. Therefore, Gpx4 suppresses lipid peroxidation through a mechanism distinct from that of lipid antioxidants. Gpx4's role in reducing phospholipid hydroperoxides in cells such as neurons is critical and indispensable. Gpx4 also serves as the master regulator of ferroptosis. We have demonstrated that Gpx4 plays a critical role in ensuring heath and survival of neurons in adult animals, such as forebrain neurons that are severely afflicted in AD. In preliminary studies, we obtained data indicating that there is a Gpx4 dysfunction in AD brains that could lead to exacerbated pathogenesis and that enhanced Gpx4 function retards cognitive impairment of AD mouse models. In this project, we will determine whether increased membrane lipid peroxidation induced by Gpx4 deficiency aggravates disease pathogenesis such as neurodegeneration, and determine the efficacy of Gpx4 overexpression in retarding cognitive impairment and neurodegeneration in AD mice. The overall hypothesis tested in this project is: Membrane lipid peroxidation aggravates A? neurotoxicity in vivo, and augmentation of Gpx4 function to suppress membrane lipid peroxidation will retard AD pathogenesis. The hypothesis will be tested by three specific aims. Aim 1 is to determine the effect of membrane lipid peroxidation induced by Gpx4 deficiency on AD pathogenesis. Aim 2 is to determine whether overexpression of Gpx4 can suppress neurodegeneration and improve cognition in AD mice. Aim 3 is to determine whether Gpx4 overexpression via transduction with viral vector can retard progression of disease in AD mice at different disease stages. Our study will establish the importance of membrane lipid peroxidation in neurodegeneration of AD and provide proof-of-concept evidence for the efficacy of Gpx4 as a target of intervention to retard progression of AD.